Interest in the percutaneous or transdermal delivery of peptides and proteins to the human body continues to grow with the increasing number of medically useful peptides and proteins becoming available in large quantities and pure form. The transdermal delivery of peptides and proteins still faces significant problems. In many instances, the rate of delivery or flux of polypeptides through the skin is insufficient to produce a desired therapeutic effect due to the binding of hydrophobic sites present on the polypeptides to lipids present in the skin. In addition, polypeptides and proteins are easily degradable during and after penetration of the skin, prior to reaching target cells.
One method of increasing the transdermal delivery of agents relies on the application of an electric current across the body surface or electrotransport. "Electrotransport" refers generally to the passage of a beneficial agent, eg, a drug or drug precursor, through a body surface such as skin, mucous membranes, nails, and the like. The transport of the agent is induced or enhanced by the application of an electrical potential, which results in the application of electric current, which delivers or enhances delivery of the agent. The electrotransport of agents into the human body may be attained in various manners. One widely used electrotransport process, iontophoresis, involves the electrically induced transport of charged ions. Electroosmosis, another type of electrotransport process, involves the movement of a solvent with the agent through a membrane under the influence of an electric field. Electroporation, still another type of electrotransport, involves the passage of an agent through pores formed by applying an electrical pulse, a high voltage pulse, to a membrane. In many instances, more than one of these processes may be occurring simultaneously to different extents. Accordingly, the term "electrotransport", is given herein its broadest possible interpretation, to include the electrically induced or enhanced transport of at least one charged or uncharged agent, or mixtures thereof, regardless of the specific mechanism(s) by which the agent is actually being transported.
Electrotransport devices generally use at least two electrodes which are in electrical contact with some portion of the skin, nails, mucous membranes, or other body surface. One electrode, commonly referred to as the "donor" or "active" electrode, is the one from which the agent is delivered into the body. The other, typically termed the "counter" or "return" electrode, serves to close the electrical circuit through the body. For example, when the agent to be delivered is a cation, ie, a positively charged ion, the anode becomes the active or donor electrode, while the cathode serves to complete the circuit. Alternatively, if an agent is an anion, ie, a negatively charged ion, the cathode is the donor electrode. Both the anode and cathode may be donor electrodes if both anionic and cationic ionic agents are delivered simultaneously. Electrotransport delivery systems generally require at least one reservoir or source of the agent to be delivered to the body. Examples of such donor reservoirs include a pouch or cavity as described in U.S. Pat. No. 4,250,878 to Jacobsen, a porous sponge or pad as described in U.S. Pat. No. 4,141,359 to Jacobsen et al, and a pre-formed gel body as described in U.S. Pat. No. 4,383,529 to Webster, among others. The pertinent portions of which are incorporated herein by reference. Such donor reservoirs are electrically connected to, and positioned between, the anode or cathode and the body surface, to provide a fixed or renewable source of one or more agents or drugs. In addition, electrotransport delivery systems also typically have an electrical power source, eg, one or more batteries, and an electrical controller designed to regulate the timing, amplitude and/or frequency of the applied electric current, and hence regulate the timing and rate of drug delivery. This power source component is electrically connected to the donor and counter electrodes. Optional electrotransport device components include a counter agent reservoir, adhesive coatings, insulating separation layers, and rate-controlling membranes.
Electrotransport delivery generally increases peptide delivery rates relative to passive or non-electrically assisted, transdermal delivery. However, further increases in transdermal delivery rates and reductions in peptide degradation during transdermal delivery are highly desirable. One method of increasing the agent transdermal delivery rate involves pre-treating the skin with, or alternatively co-delivering with the beneficial agent, a skin permeation enhancer. The term "permeation enhancer" is broadly used herein to describe a substance which, when applied to a body surface through which the agent is delivered, enhances its electrotransport flux. The mechanism may involve a reduction of the electrical resistance of the body surface to the passage of the agent therethrough, an increase in the permeability of the body surface, the creation of hydrophilic pathways through the body surface, and/or a reduction in the degradation of the agent (eg, degradation by skin enzymes) during electrotransport. The term "body surface," as used herein, refers generally to the skin, mucous membranes, and nails of an animal, and to the outer surface of a plant.
The preferred form in which an agent and an enhancer are delivered generally determines the type of delivery system to be used, and vice versa. That is, the selection of a "passive" system which delivers the agent by diffusion or an electrically powered system which delivers the agent by electrotransport will be mostly determined by the form of the agent. For example, with passive delivery systems, it has generally been recognized that the agent is preferably delivered in either its free base or acid form, rather than in the form of a water soluble salt. (eg, U.S. Pat. No. 4,588,580 to Gale et al, at column 3, lines 6-20). On the other hand, with electrotransport delivery devices, it has been recognized that the drug should generally be soluble in water. (eg, U.S. Pat. No. 4,474,570 to Ariura et al, at column 7, lines 5-7). It is generally believed that the pathways for passive and electrotransported transdermal drug delivery are different, with passive delivery occurring through lipid regions, ie, hydrophobic regions, of the skin and electrotransport delivery occurring through hydrophilic pathways or pores such as those associated with hair follicles and sweat glands. Thus, the preferred form of a drug for passive delivery is generally hydrophobic, eg, free base form, whereas the preferred form of a drug for electrotransport delivery is hydrophilic, eg, water soluble salt form.
The form of the permeation enhancer used to enhance transmembrane agent flux is likewise dependent on its mode of delivery. Thus, relatively hydrophobic non-ionic surfactants and organic solvents have been used as passive agent permeation enhancers. U.S. Pat. No. 4,568,343, for example, utilizes poly(ethylene glycol) as a permeation enhancer for passive transdermal delivery. U.S. Pat. No. 4,994,439 to Longenecker et al uses bile salts or fusidates with certain non-ionic detergents for the passive delivery of drugs through nasal mucosal membranes. Similarly, U.S. Pat. No. 4,153,689 discloses the passive nasal administration of insulin with the aid of non-ionic surfactants having a hydrophile-lipophile balance (HLB) of 9 to 22 at a pH from 2.5 to 4.7. U.S. Pat. No. 5,120,716 to Miyazawa et al utilizes a passive percutaneous composition including both an N-containing agent such as non-ionic, amphoteric, semi-polar, or cationic surfactants and a non-ionic agent lacking nitrogen atoms. UK Patent 2,127,689 A to Sandoz utilizes benzalkonium chloride and a non-ionic surfactant suitable for use in the nasal mucosa for the passive nasal administration of calcitonin.
On the other hand, relatively hydrophilic permeation enhancers such as ionic surfactants have been used to enhance electrotransport drug delivery. (See, for example, U.S. Pat. No. 4,722,726 to Sanderson et al).
A variety of surfactants have been explored as permeation enhancers for both passive and electrotransport drug delivery. However, the prior art has not recognized a class of permeation enhancers specifically suited for the electrotransport delivery of agents having hydrophobic sites thereon, such as polypeptides or proteins. Thus, there is still a need to provide compositions, which are suitable for increasing the flux of agents having some hydrophobic sites when administered with the aid of an electric current.